Quinoline derivatives

ABSTRACT

A process for preparing dihydro compounds of formula I, by rearranging compounds of formula II, e.g. in the presence of acids or noble metal catalysts, is described. The compounds II may be prepared from intermediates of formula III. ##STR1## In these formulae R 1 ,R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are the same or different and represent hydrogen, or alkyl, cycloalkyl, aralkyl, or aryl radicals any of which radicals may be substituted, or R 1  and R 2  taken together or R 2  and R 3  taken together, form a 5, 6 or 7 membered ring which may be saturated or unsaturated and substituted or unsubstituted, R 4  and R 5  may also represent alkoxy, or cycloalkoxy, n is 1, 2 or 3 and, if more than one R 4  radical is present the R 4  radicals may be the same or different and R 6  and R 7  represent hydrogen, alkyl, cycloalkyl, or aralkyl radicals. 
     Most of the compounds I, II and III are novel and are claimed. They are intermediates for anti-ulcer agents.

The invention relates to quinoline derivatives and especially to5,6-dihydroquinolines and related compounds, to novel processes forpreparing them and to novel compounds obtained by such processes.

In one aspect the invention provides a process for preparing dihydrocompounds of formula I ##STR2## and acid addition salts thereof, whereinR¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are the same or different and representhydrogen, or alkyl, cycloalkyl, aralkyl, or aryl radicals any of whichradicals may be substituted, or R¹ and R² taken together or R² and R³taken together, form a 5, 6 or 7 membered ring which may be saturated orunsaturated and substituted or unsubstituted, R⁴ and R⁵ may alsorepresent alkoxy, or cycloalkoxy, n is 1, 2 or 3 and, if more than oneR⁴ radical is present the R⁴ radicals may be the same or different,which process comprises re-arranging a compound of formula II ##STR3##wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and n are as defined above.

The re-arrangement of compound II to compound I may be carried out underacidic or basic conditions. Examples of acid catalysts which may be usedare organic acids such as carboxylic acids e.g. lower alkylcarboxylicacids such as acetic acid, inorganic acids such as phosphoric acid, orpolyphosphoric acid, Lewis acids e.g. boron trifluoride, zinc chlorideor acid anhydrides e.g. acetic anhydride. Alternatively a noble metalcatalyst, e.g. a Pt or Pd catalyst may be used, optionally in thepresence of a weak base such as sodium acetate or a heterogeneous orhomogeneous catalyst, e.g. PdCl₂ (PhCN)₂, RhCl[(C₆ H₅)₃ P]₃ Ru₃ (CO)₁₂or IrCl(CO)[(C₆ H₅)₃ P]₂.

Preferably the rearrangement is carried out in the presence of aceticacid, a noble metal catalyst in the presence of a base, or a Lewis acid.

The above mentioned acids may be used to prepare acid addition salts ofcompounds of formula I and other compounds of the invention.

When any of R¹, R², R³, R⁴, R⁵, R⁶ or R⁷ is an alkyl radical it ispreferred that this is a lower alkyl radical of 1 to 6 carbon atomswhich may have a straight or branched chain e.g. methyl, ethyl, n- andiso-propyl and n-, s- and t-butyl. When R⁴ or R⁵ is an alkoxy radical itis preferred that the radical is lower alkoxy in which the alkyl portionhas 1 to 6 carbon atoms and is as defined above, for an alkyl radical.

When any of R¹, R², R³, R⁴, R⁵, R⁶ or R⁷ is a cycloalkyl radical suchradicals having from 4 to 6 carbon atoms are preferred i.e. cyclobutyl,cyclopentyl or cyclohexyl. If R⁴ or R⁵ is cycloalkoxy the cycloalkylportion of this group may be as just described for a cycloalkyl group.

An aralkyl group may be an arylalkyl group in which the alkyl portion isas described herein for an alkyl group. Preferred aralkyl groups arethose having from 7-12 carbon atoms.

When any of R¹, R², R³, R⁴ or R⁵ is an aryl group it is preferablyphenyl or substituted phenyl (substituted by e.g. alkyl, alkoxy ortrifluoromethyl). The aryl portion of an aralkyl group may besubstituted as described for a phenyl group.

The invention includes novel compounds of formula I and their acidaddition salts wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and n are as definedabove, with the proviso that R⁶ and R⁷ are not both hydrogen when R¹,R², R³, R⁴ and R⁵ are all hydrogen.

Preferred compounds are those of formula IA ##STR4## or an acid additionsalt thereof, wherein R¹ is lower alkyl and R⁶ and R⁷ are selected fromhydrogen and lower alkyl. A particular example is3,8-dimethyl-5,6-dihydroquinoline or an acid addition salt thereof.

Some starting materials of formula II are also novel and these areincluded in the invention. They are compounds of formula II and theiracid addition salts wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and n are asdefined above in connection with formula I with the provisos that (1)when R¹, R², R³, R⁴ and R⁵ are all hydrogen, R⁶ and R⁷ are not bothhydrogen and (2) when R¹ and R³ are both phenyl and when R¹ is methyland R⁴ is methyl then R⁶ and R⁷ are not both methyl.

A preferred sub group of these compounds are those of formula IIA##STR5## or an acid addition salt thereof wherein R¹ is lower alkyl andR⁶ and R⁷ are selected from hydrogen and lower alkyl. Examples are5,6,7,8-tetrahydro-3-methyl-8-(2-propylidene)quinoline,5,6,7,8-tetrahydro-3-methyl-8(methylene)quinoline, and their acidaddition salts.

The starting materials of formula II may be prepared by dehydration ofthe corresponding compounds of formula III ##STR6## wherein R¹, R², R³,R⁴, R⁵, R⁶, R⁷ and n are as defined above.

The dehydration may be carried out with usual dehydrating agents e.g.polyphosphoric acid or with acetic anhydride, (in which case anintermediate acetylated derivative may be formed, from which acetic acidis eliminated to give the compound of formula II).

Some compounds of formula III are also novel and are included in theinvention. These are compounds of formula III and their acid additionsalts and esters of carboxylic acids wherein R¹, R², R³, R⁴, R⁵ and nare as defined above in connection with formula I and R⁶ and R⁷ areother than hydrogen when R¹, R², R³, R⁴ and R⁵ are all hydrogen and R⁶and R⁷ are not both methyl when R⁴ is methyl.

Preferred compounds of formula III are the sub group of formula IIIA##STR7## or an acid addition salt thereof wherein R¹ is lower alkyl andR⁶ and R⁷ are selected from hydrogen, lower alkyl, cycloalkyl, or loweraralkyl radicals. Examples are[8R*]-5,6,7,8-tetrahydro-8-([2S*]-2-(2-hydroxy-1-phenyl)propyl)-3-methylquinoline,5,6,7,8-tetrahydro-8-(2(2-hydroxy)propyl-3-methylquinoline and theiracid addition salts.

The compounds of formula III may be prepared by treatment of a compoundof formula IV ##STR8## wherein R¹, R², R³, R⁴, R⁵ and n are as definedin connection with formula I, and M is hydrogen, an alkali metal (e.g.sodium, potassium or lithium) or MgHal, where Hal is chlorine, bromineor iodine, with a carbonyl compound of formula V ##STR9## wherein R⁶ andR⁷ are as defined in connection with formula I, with the proviso thatwhen R⁶ and R⁷ are both hydrogen then M is hydrogen.

The present invention also provides a new process for preparingcompounds of formula I wherein R⁶ and R⁷ are hydrogen from compounds offormula IV.

It has been reported by Hahn and Epsztajn, Roczniki Chemie, 1964, 38,989 that treatment of VIa or IVb ##STR10## with polyphosphoric acidgives the corresponding methylene compounds VIIa and VIIb ##STR11##exclusively with no corresponding methyl isomer being formed. We havesurprisingly found that compounds of formula I wherein R⁶ and R⁷ arehydrogen, can be obtained by treatment of a compound of formula IVwherein M is hydrogen with formaldehyde (which may be in the form of aparaformaldehyde) in the presence of an organic acid anhydride, e.g.acetic anhydride. It is believed that an intermediate compound offormula III wherein R⁶ and R⁷ are both hydrogen is formed initially,this dehydrates to give a compound of formula II wherein R⁶ and R⁷ arehydrogen and the compound of formula II rearranges to give a compound offormula I wherein R⁶ and R⁷ are hydrogen. Previously compounds offormula I were relatively inaccessible--see Rosen and Weber J. Org.Chem. 1977, 42, 47-50 who obtained 8-methyl-5,6-dihydroquinoline bypyrolysis of 1-methyl-1(α-pyridinyl)-1,3-butadiene. However pyrolysis isnot a satisfactory method of preparation especially for moleculescarrying a variety of substituents.

Compounds of formula II may also be prepared by the Peterson reaction (JOrganic Chem 1968, 780; Carey and Toler ibid, 1976, 41, 1966, Hudrik &Peterson J Amer Chem Soc 1975, 97, 1464)--see the scheme below.##STR12##

An oxo compound of formula VIII is treated with a silicon compound IXunder the conditions of the Peterson reaction to give a silyl compound Xwhich is treated under acidic or basic conditions to give compound II.If the conditions of work up are acidic (e.g. sulphuric acid ortrifluoroacetic acid) then compound X will usually be converted firstinto a compound X where M is H, but basic conditions (e.g. sodium orpotassium hydride) and use of fluoride ions (e.g. KF or LiF) usuallyresult in direct formation of compound II. In the silicon compound IX,R⁶ and R⁷ are as previously defined in connection with formula I, M isan alkali metal especially lithium or MgHal where Mg denotes magnesiumand Hal is chlorine, bromine or iodine, and the three R radicals may bethe same or different and alkyl, cycloalkyl, aralkyl or aryl (whichradicals may be as previously defined for R¹, R² etc.) or R is selectedfrom electron donating substituents including alkoxy, cycloalkoxy,aralkoxy, aryloxy, alkylthio, cycloalkylthio, aralkylthio or arylthio,the group R^(b) R^(c) N- wherein R^(b) and R^(c) are selected fromalkyl, cycloalkyl, aryl and aralkyl (which radicals may be as previouslydefined for R¹, R² etc.) or R^(b) and R^(c) may be joined to form aheterocyclic ring with the nitrogen atom (e.g. a piperidinyl orpyrrolidinyl ring, which may be substituted e.g. by alkyl). It ispreferred that SiR₃ is triloweralkylsilyl e.g. trimethylsilyl ortriarylsilyl e.g. triphenylsilyl.

When the R radical is alkoxy or cycloalkoxy these radicals may be asdefined above for R⁴ and R⁵. Aralkoxy and aryloxy radicals for R may besuch radicals in which the aralkyl or aryl portions are as defined abovefor aralkyl or aryl radicals. Similarly when R radicals are alkylthio,cycloalkylthio, aralkylthio, or arylthio, the alkyl, cycloalkyl, aralkylor aryl portions of these radicals may be as defined above for alkyl,cycloalkyl, aralkyl or aryl radicals.

The silicon compound IX starting materials may be prepared fromcorresponding compounds R₃ SiCHR⁶ R⁷ by standard methods. The startingmaterials of formula VIII may be prepared as described in UK PatentSpecification No. 1460457 or by analogous methods.

In a variation of the above reaction the compounds of formula II may beprepared by the following scheme: ##STR13##

A silicon compound of formula XI, where R¹, R², R³, R⁴, R⁵, R and n areas previously defined and X is hydrogen, sodium, potassium or lithium isreacted with a carbonyl compound R⁶ R⁷ CO to obtain a silyl intermediateof formula XII which is converted to compound II by acid or basetreatment as described for the previous reaction scheme. The startingcompound XI may be prepared as described in U.S. patent application Ser.No. 506,277 filed 21 June 1983, or by analogous methods. Briefly acompound of formula ##STR14## where M is sodium, potassium or lithium istreated with a silylating agent of formula R₃ SiHal where R is asdefined above and Hal is chlorine, bromine or iodine, to obtain acompound of formula XI wherein X is hydrogen and if desired treatingthis with a metal compound R*M where M is sodium, potassium or lithiumand R* is alkyl, cycloalkyl, aralkyl or aryl or an amine residue toobtain a compound of formula XI where X is sodium, potassium or lithium.

Alternatively compounds of formula II may be prepared by the Wittigreaction (see Peterson loc cit for references thereto). ##STR15##

The Wittig phosphorus reagent is prepared by reacting Ph₃ P with acompound R⁶ R⁷ CHBr.

Compounds of formula I may be used as intermediates for the preparationof the corresponding compounds of formula XIV ##STR16##

Compounds of formula XIV are intermediates for other compounds withanti-ulcer or anti-secretory activity eg. the compounds of UK PatentSpecification No. 1432378.

The invention is illustrated by the following Examples.

EXAMPLE 1 3,8-Dimethyl-5,6,7,8-tetrahydroquinoline

A mixture of 3-methyl-5,6,7,8-tetrahydroquinoline (100 ml)paraformaldehyde (30 g) and acetic anhydride (100 ml) was heated atreflux for 30 hours. The residue was distilled to give a mixture ofstarting tetrahydroquinoline and 3,8-dimethyl-5,6-dihydroquinoline (40g) bp. 126°-180°/15 mm. Chromatography on silica gel (500 g, Woelmactive, 100-200) using di-isopropyl ether gave3,8-dimethyl-5,6-dihydroquinoline (22 g).

A solution of the dihydroquinoline (22 g) in ethanol (200 ml.) washydrogenated over 10% palladium on carbon (1 g) at 25° and 1 atmosphere.After the theoretical uptake had occurred (1.5 hours) the catalyst wasremoved by filtration, the filtrate evaporated and the residue distilledto give the title tetrahydroquinoline (22 g) bp. 124°/15 mm

C₁₁ H₁₅ N requires: C, 81.9; H, 9.4; N, 8.7%. Found: C, 81.9, H, 9.1, N,8.3%

The catalyst in this example is a mixture of acetic anhydride and aceticacid, the acetic acid being produced in situ.

EXAMPLE 2 Compound Present

The reaction described in Example 1, 1st paragraph, was followed in atime course experiment, samples being taken at intervals and compositionanalysed by glc. (Pye 104 C20M T=200°) Results were as follows:

    ______________________________________                                         ##STR17##                                                                     ##STR18##                                                                             Starting Material                                                     Time      (A)          (B)    (C)                                            ______________________________________                                         11/2hours 20%          66%     7%                                            21/2hours  21%          61%    11%                                            41/4hours  22%          51%    20%                                            61/2hours  23%          42%    26%                                            30 hours   22%          0      68%                                            ______________________________________                                    

EXAMPLE 3

The reaction described in Example 1, 1st paragraph, was repeatedemploying various catalysts. The results are shown in the followingtable (for structures of compounds B and C--see Example 2).

Isomerisation of Compound B to Compound C using various Catalysts

    ______________________________________                                        Catalyst/Reaction  Reaction time                                                                            Percentage of                                   Conditions         (hours)    Compound C                                      ______________________________________                                        CH.sub.3 CO.sub.2 H, reflux                                                                      30         100                                             NaOAc, 5% Pd--C, EtOH, reflux                                                                    21.6       85.4                                            BF.sub.3 --Et.sub.2 O, dioxan, reflux                                                            24         83                                              PPA, 100°    1.5       76.sup.a                                        H.sub.3 PO.sub.4, H.sub.2 O, reflux                                                              21.6       25.1                                            ZnCl.sub.2, dioxan, reflux                                                                       30         22.5                                            (CH.sub.3 CO).sub.2 O, reflux                                                                    30         5                                               KOH, EtOH, 22°                                                                            30         5                                               ______________________________________                                         .sup.a Severe decomposition of compound C was observed after 2 hours.         PPA = Polyphosphoric acid                                                

EXAMPLE 4[8R*]-5,6,7,8-tetrahydro-8-([2S*]-2-(2-hydroxy-1-phenyl)propyl)-3-methylquinoline##STR19##

To a mixture of 5,6,7,8-tetrahydro-3-methylquinoline (20 g) and toluene(100 ml) was added 1.63 molar n-BuLi in hexane (93 ml) at -40° C. Theresulting anion solution was added to a mixture of phenylacetone (50 ml)and toluene (100 ml) at -40° C. The solution was allowed to warm to roomtemperature and the excess n-BuLi was quenched by adding 2N HCl (90 ml).The excess solvent was removed by evaporation. The resultant aqueousmixture was basified with saturated aqueous NaHCO₃ solution andextracted with EtOAc (3×100 ml). The extracts were dried (MgSO₄) and thesolvent removed by evaporation. The mixture of products were separatedby chromatography [SiO₂ ; cyclohexane-CH₃ CO₂ CH₃ (4:1)]. Upon removalof the solvent by evaporation the product crystallised to give the titlecompound (2.25 g), m.p. 99°-101° C. (Found: C, 81.1; H, 8.1; N, 4.7.C.sub. 19 H₂₃ NO requires C, 81.1; H, 8.2; N, 5.0%).

EXAMPLE 5[8R*]-5,6,7,8-tetrahydro-8-([2R*]-2-(2-hydroxy-1-phenyl)propyl)-3-methylquinoline##STR20##

To a mixture of 5,6,7,8-tetrahydro-3-methylquinoline (20 g) and toluene(100 ml) was added 1.63 molar n-BuLi in hexane (93 ml) at -40° C. Theresulting anion solution was added to a mixture of phenylacetone (50 ml)and toluene (100 ml) at -40° C. The resulting solution was allowed towarm to room temperature. The excess n-BuLi was quenched by adding2N-HCl (90 ml). The aqueous layer was separated, basified with saturatedaqueous NaHCO₃ solution, and extracted with Et₂ O (3×100 ml). Theethereal extracts were dried (MgSO₄) and the solvent removed byevaporation. The mixture of products was separated by chromatography[SiO₂ ; cyclohexane-methyl acetate (80:20)]. The solvent was removed byevaporation and the residue dissolved in Et₂ O, to which an etherealsolution of HCl (50 ml) was added. The precipitate was collected byfiltration, washed with Et₂ O, and dried in vacuo to give the titlecompound as a hydrochloride 11/2 hydrate (2.09 g) m.p. 98°-100° C.(Found: C, 66.2; H, 7.5; N, 3.9. C₁₉ H₂₃ NO.HCl.3/2H₂ O requires C,66.2; H, 7.9; N, 4.1%).

EXAMPLE 6 5,6,7,8-tetrahydro-8-(1-hydroxyethyl)-3-methylquinoline##STR21##

To a mixture of 5,6,7,8-tetrahydro-3-methylquinoline (20 g) and dry THF(150 ml) was added 1.63 molar n-BuLi in hexane (108 ml) at -30° C. Theresulting anion solution was added to a solution of acetaldehyde (50 ml)in anhydrous THF (50 ml) at -30° C. The solution was allowed to warm toroom temperature. The excess n-BuLi was quenched with 2N-HCl (20 ml).The excess acetaldehyde and solvent were removed by evaporation. Theresultant aqueous mixture was basified with saturated aqueous NaHCO₃solution and extracted with Et₂ O (3×100 ml). The ethereal extracts weredried (MgSO₄) and the solvent removed by evaporation. The mixture ofproducts was separated by chromatography (SiO₂ ; EtOAc). The solvent wasremoved by evaporation and the residue dissolved in Et₂ O to whichethereal HCl (50 ml) was added. The product was removed by filtration,washed with Et₂ O and dried in vacuo to give the title compound as thehydrochloride 1/4 hydrate (1.13 g) m.p. 172°-175° C. (Found: C, 62.4; H,7.9; N, 6.0 C₁₂ H₁₇ NO.HCl.1/4H₂ O requires C, 62.1; N, 8.0; N, 6.0%).

EXAMPLE 7 5,6,7,8-Tetrahydro-8-(2(2-hydroxy)propyl-3-methylquinoline##STR22##

To a mixture of 5,6,7,8-tetrahydro-3-methylquinoline (23.44 g, 159 mmol)and toluene (200 ml) was added 1.63 molar n-BuLi in hexane (108 ml) at-40°. After 15 mins. the resulting anion solution was added to asolution of acetone (100 ml) in toluene (200 ml). The solution wasallowed to warm to room temperature and was treated with 2N-HCl (90 ml).The excess acetone was removed by evaporation in vacuo. The resultantaqueous mixture was basified with saturated aqueous NaHCO₃ solution andextracted in Et₂ O (3×100 ml). The ethereal extracts were dried (MgSO₄)and the solvent removed by evaporation in vacuo. The mixture of productswere separated by chromatography [SiO₂ ; EtOAc-petrol (1:4)] to give thefree base (7.303 g, 22%) of the title compound as a red oil.

A small quantity of the free base (0.744 g) was dissolved in Et₂ O andtreated with ethereal HCl. The product was removed by filtration, washedwith Et₂ O, and dried in vacuo to give the title compound as thehydrochloride, m.p. 140°-144°. (Found: C, 63.2; H, 8.3; N, 5.5. C₁₃ H₁₉NO.HCl.1/4H₂ O requires C, 63.4; H, 8.4; N, 5.7%).

EXAMPLE 8 5,6,7,8-Tetrahydro-3-methyl-8-(2-propylidene)quinoline##STR23## Experimental Details

A mixture of 5,6,7,8-tetrahydro-8-(2(2-hydroxy)propyl)-3-methylquinoline(3.044 g, 14.8 mmol) and polyphosphoric acid (20 g) was vigorouslystirred at 80°-90° for 50 mins. and then poured into saturated aqueousNa₂ CO₃ solution (200 ml). The aqueous solution was extracted with Et₂ O(2×100 ml) and the ethereal extracts dried (MgSO₄) and evaporated invacuo to give an oil. Purification by column chromatography [SiO₂ ;hexane-propan-2-ol (1:1)] and bulb-to-bulb distillation gave the titlecompound (1.855 g, 67%) as a colourless oil, b.p. 150°-5°/0.1 mm Hg(Found: C, 83.25; H, 9.3; N, 7.5 C₁₃ H₁₇ N requires C, 83.4; H, 9.15; N,7.5%).

We claim:
 1. A dihydro compound of formula I ##STR24## and acid additionsalts thereof, wherein R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are the same ordifferent and represent hydrogen, or lower alkyl, cycloalkyl,loweraralkyl, or phenyl radicals any of which radicals may besubstituted by lower alkyl, lower alkoxy or -CF₃, or R¹ and R² takentogether or R² and R³ taken together, form a 5, 6 or 7 memberedsaturated ring R⁴ and R⁵ may also represent loweralkoxy, or cycloalkoxy,n is 1, 2 or 3 and, if more than one R⁴ radical is present the R⁴radicals may be the same or different and R⁶ and R⁷ representloweralkyl, cycloalkyl, or loweraralkyl radicals with the proviso thatR⁶ and R⁷ are not both hydrogen when R¹, R², R³, R⁴ and R⁵ are allhydrogen.
 2. A compound of formula ##STR25## or an acid addition saltthereof, wherein R¹ is lower alkyl and R⁶ and R⁷ are selected fromhydrogen and lower alkyl.
 3. 3,8-Dimethyl-5,6-dihydroquinoline or anacid addition salt thereof.
 4. A dihydro compound of formula I ##STR26##and pharmaceutically acceptable acid addition salts thereof, wherein R¹,R², R³, R⁴, R⁵, R⁶ and R⁷ are the same or different and representhydrogen, or lower alkyl, cycloalkyl, loweraralkyl, or phenyl radicalsany of which radicals may be substituted by lower alkyl, lower alkoxy ortrifluoromethyl, or R¹ and R² taken together or R² and R³ takentogether, form a 5, 6 or 7 membered saturated ring, R⁴ and R⁵ may alsorepresent loweralkoxy, or cycloalkoxy, and, if more than one R⁴ radicalis present the R⁴ radicals may be the same or different, with theprovisos that (1) R⁶ and R⁷ are not both hydrogen when R, R², R³, R⁴ andR⁵ are all hydrogen and (2) when R², R³, R⁴ and R⁵ are all hydrogen andR⁶ and R⁷ are selected from hydrogen and loweralkyl, then R¹ is otherthan loweralkyl.